U.S. patent number 6,090,822 [Application Number 09/162,011] was granted by the patent office on 2000-07-18 for treatment of cytokine growth factor caused disorders.
Invention is credited to Solomon B. Margolin.
United States Patent |
6,090,822 |
Margolin |
July 18, 2000 |
Treatment of cytokine growth factor caused disorders
Abstract
In preferred embodiments, a method of prevention and treatment
of disorders caused by enhanced proliferation and enhanced
biosynthesis caused by cytokine growth factors in humans and other
animals, the method including: administering to a human or other
animal an effective dose of a pharmaceutical substance including an
N-substituted 2(1H) pyridone and/or an N-substituted 3(1H)
pyridone; and a composition for prevention and treatment of
disorders caused by enhanced proliferation and enhanced
biosynthesis caused by cytokine growth factors in humans and other
animals, the composition including: a pharmaceutical preparation
including an effective dose of an N-substituted 2(1H) pyridone
and/or an N-substituted 3(1H) pyridone.
Inventors: |
Margolin; Solomon B. (Dallas,
TX) |
Family
ID: |
27378058 |
Appl.
No.: |
09/162,011 |
Filed: |
September 28, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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913202 |
Sep 3, 1997 |
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PCTUS9602737 |
Mar 4, 1996 |
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397962 |
Mar 3, 1995 |
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Current U.S.
Class: |
514/313; 514/334;
514/336; 514/341; 514/342; 514/345 |
Current CPC
Class: |
A61K
31/4418 (20130101); A61K 31/4436 (20130101); A61K
31/4709 (20130101); A61K 31/444 (20130101); A61K
31/4439 (20130101) |
Current International
Class: |
A61K
31/444 (20060101); A61K 31/4418 (20060101); A61K
31/4427 (20060101); A61K 31/4436 (20060101); A61K
31/4439 (20060101); A61K 31/4709 (20060101); A61K
031/44 (); A61K 031/47 () |
Field of
Search: |
;514/345,336,334,341,342,313 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Goldberg; Jerome D.
Attorney, Agent or Firm: Crozier; John H.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
The present application is a continuation-in-part of U.S.
application Ser. No. 08/913,202, filed Sep. 3, 1997, abandoned,
which is a continuation of Patent Cooperation Treaty Application
No. PCT/US96/02737, filed Mar. 4, 1996, which is a
continuation-in-part of U.S. application Ser. No. 08/397,962 filed
Mar. 3, 1995, abandoned.
Claims
What is claimed is:
1. A method of prevention and treatment of disorders caused by
enhanced proliferation and enhanced biosynthesis caused by cytokine
growth factors, sensitive to the compounds below, in humans and
other animals, in need thereof, comprising: administering to a
human or other animal an effective dose of a pharmaceutical
substance including an N-substituted 2(1H) pyridone having the
following general structural formula: ##STR3## where; R1 is
selected from the group consisting of (1) an alkyl group, with R3
hydrogen, and (2) hydrogen with R3 consisting of an alkyl group; A
is an aryl group; and R2 and R4 are hydrogen;
and/or an N-substituted 3(1H) pyridone having the following general
structural formula: ##STR4## where: R2 is selected: from the group
consisting of (1) an alkyl group, with R3 hydrogen and (2)
hydrogen, with R3 consisting of an alkyl group; A is an aryl group;
and R1 and R4 are hydrogen.
2. A method of prevention and treatment, as defined in claim 1,
wherein said pharmaceutical substance includes one or more
compounds selected from the group consisting of:
5-Methyl-1-phenyl-2-(1H) pyridone
5-Methyl-1-(3-nitrophenyl-2)-(1H) pyridone
5-Methyl-1-(4'-methoxyphenyl)-2-(1H) pyridone
5-Methyl-1-p-tolyl-2-(1H) pyridone
5-Methyl-1-(3'-trifluoromethylphenyl)-2-(1H) pyridone
1-(4'Chlorophenyl)-5-Methyl-2)-(1H) pyridone
5-Methyl-1-(2'-naphthyl)-2-(1H) pyridone
5-Methyl-1-(1'naphthyl)-2-(1H) pyridone
3-Methyl-1-phenyl-2-(1H) pyridone
3-Ethyl-1 phenyl-2-(1H) pyridone
6-Methyl-1-phenyl-2-(1H) pyridone
3,6-Dimethyl-1-phenyl-2-(1H) pyridone
5-Methyl-1-(2'-Thienyl)-2-(1H) pyridone
1-(2'-Furyl)-5-Methyl-2-(1H) pyridone
5-Methyl-1-(5'-quinolyl)-2-(1H) pyridone
5-Methyl-1-(4'-pyridyl)-2-(1H) pyridone
5-Methyl-1-(3'-pyridyl)-2-(1H) pyridone
5-Methyl-1-(2'-pyridyl)-2-(1H) pyridone
5-Methyl-1-(2'-quinolyl)-2-(1H) pyridone
5-Methyl-1-(4-quinolyl)-2-(1H) pyridone
5-Methyl-1-(2'-thiazolyl)-2-(1H) pyridone
1-(2'-Imidazolyl)-5-Methyl-2-(1H) pyridone
5-Ethyl-1-phenyl-2-(1H) pyridone
1-Phenyl-2-(1H) pyridone
1-(4'-Nitrophenyl)-2-(1H) pyridone
1,3-Diphenyl-2-(1H) pyridone
1-Phenyl-3-(4'-chlorophenyl)-2-(1H) pyridone
1,3-Diphenyl-5-methyl-2-(1H) pyridone
3-(4'-Chlorophenyl)-5-Methyl-1-phenyl-2-(1H) pyridone
5-Methyl-3-phenyl-1-(2'-thienyl)-2-(1H) pyridone
5-Methyl-1-phenyl-3-(1H) pyridone
5-Methyl-1-(4'-methoxyphenyl)-3-(1H) pyridone
5-Methyl-1-p-tolyl-3-(1H) pyridone
1-(4'-Chlorophenyl)-5-methyl-3-(1H) pyridone
5-Methyl-1-(2'-naphthyl)-3-(1H) pyridone
4-Methyl-1-phenyl-3-(1H) pyridone
6-Methyl-1-phenyl-3-(1H) pyridone
5-Methyl-1(2'-Thienyl)-3-(1H) pyridone
1-(2'-Furyl)-5-methyl-3-(1H) pyridone
5-Methyl-1-(5'-quinolyl)-3-(1H) pyridone
5-Methyl-1-(3'-pyridyl)-3-(1H) pyridone
5-Methyl-1-(2'-pyridyl)-3-(1H) pyridone
5-Methyl-1-(2'-quinolyl)-3-(1H) pyridone
5-Ethyl-1-phenyl-3-(1H) pyridone
1-Phenyl-3-(1H) pyridone.
3. A method of prevention and treatment, as defined in claim 1,
wherein: said pharmaceutical substance is administered to a mammal
in the amount of from about 20 to about 150 mg/kg body weight per
day.
4. A method of prevention and treatment, as defined in claim 1,
wherein: said pharmaceutical substance is administered in a form
selected from the group consisting of: capsules, tablets, powders,
granules, syrups, aerosols, injectable fluids, pills, creams,
ointments, inhalable fluids, eye drops, and suppositories.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the prevention and treatment of
disorders in humans and other animals generally and, more
particularly, but not by way of limitation, to compositions and
methods for prevention and treatment of disorders caused by
enhanced proliferation and enhanced biosynthesis caused by cytokine
growth factors.
2. Background Art
The clinical applications for chemical substances (new drugs) which
block or inhibit the activity of four cytokine growth factors and
their closely related chemical peptides, transforming growth factor
(TGF-Beta-1), platelet-derived growth factor (PDGF), epidermal
growth factor (EGF), and fibroblast growth factor (FGF), will have
extraordinary medicinal applications in the following major
proliferative disorders: immunology (allergy, auto-immunity,
immunosuppression), fibrotic lesions (all vital organs), infections
of virus origin (herpes, Roux virus, etc.), tissue injuries caused
by bacterial or fungal infections, and tissue injuries caused by
trauma, extravasation from blood vessels or blood vessel rupture
with hemorrhage into adjacent tissues, and, finally, occlusions
(clots or stenosis) of blood vessels.
Each of the above conditions readily triggers massive proliferation
and activation of mesenchymal or mesenchymal-like cells resulting
in extensive inflammation, dislocation, and deformities of blood
vessels and organ structures. These are visualized and experienced
clinically in the form of disabling organ (i.e., lungs, kidneys,
skin, joints, cardiac, brain, etc.) dysfunction.
A perspective of the possibilities is seen in the review articles
of the role of TGF-Beta-1, along with some reference to the other
growth factors as presented by Border and Noble, "Transforming
Growth Factor [Beta] in Tissue Fibrosis", The New England Journal
of Medicine, Nov. 10, 1994, pages 1286-1292; also, Varga and
Jimenez, "Modulation of Collagen Gene Expression: Its Relation to
Fibrosis in Systemic Sclerosis and Other Disorders", Annals of
Internal Medicine, Vol. 122, No. 1, January 1995.
Accordingly, it is a principal object of the present invention to
provide compositions and methods for prevention and treatment of
disorders caused by enhanced proliferation and enhanced
biosynthesis caused by cytokine growth factors.
Other objects of the present invention, as well as particular
features, elements, and advantages thereof, will be elucidated in,
or be apparent from, the following description and the accompanying
drawing figures.
SUMMARY OF THE INVENTION
The present invention achieves the above objects, among others, by
providing, in preferred embodiments, a method of prevention and
treatment of disorders caused by enhanced proliferation and
enhanced biosynthesis caused by cytokine growth factors in humans
and other animals, comprising: administering to a human or other
animal an effective dose of a pharmaceutical substance including an
N-substituted 2(1H) pyridone and/or an N-substituted 3(1H)
pyridone; and a composition for prevention and treatment of
disorders caused by enhanced proliferation and enhanced
biosynthesis caused by cytokine growth factors in humans and other
animals, comprising: a pharmaceutical preparation including an
effective dose of an N-substituted 2(1H) pyridone and/or an
N-substituted 3(1H) pyridone.
BRIEF DESCRIPTION OF THE DRAWING
Understanding of the present invention and the various aspects
thereof will be facilitated by reference to the accompanying
drawing figures, submitted for purposes of illustration only and
not intended to define the scope of the invention, on which:
FIGS. 1A-6 illustrate the effects of prevention and treatment with
pirfenidone of disorders caused by cytokine growth factors in
humans and other animals.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
5-Methyl-1-phenyl-2-(1H)-pyridone, "pirfenidone", and related
substances inhibit the proliferation and activating actions of the
aforementioned four growth factors and as a result, prevent or
correct the lesions generated in the above cited categories:
immunology (allergy, auto-immunity, immunosuppression), fibrotic
lesions (all vital organs), infections of virus origin (herpes,
Roux virus, etc.), tissue injuries caused by bacterial or fungal
infections, and tissue injuries caused by trauma, extravasation
from blood vessels or blood vessel rupture with hemorrhage into
adjacent tissues, and, finally, occlusions (clots or stenosis) of
blood vessels. Pirfenidone and related drugs inhibit these
pathogenic actions in a pharmacological manner at doses which are
much smaller than those which produce toxic effects in in vitro
tissue cultures and living animals or humans.
Some details of the roles that these four growth factors play in
the cited pathogenesis are described in the following
paragraphs:
In the pathogenesis of proliferative diseases, excessive cell
proliferation occurs as a result of the presence of various
cytokine growth factors, such as TGF-Beta-1 platelet-derived growth
factor (PDGF), epidermal growth factors (EGF), and fibroblast
growth factor (FGF). For example, growth factors produced by
cellular constituents in the blood, and by the damaged arterial
vessel wall mediate the proliferation of smooth muscle cells in
vascular restenosis.
Other cytokines growth factors involved with TGF-Beta-1 in tissue
remodeling after injury are platelet derived growth factor (PDGF)
and basic fibroblast growth factor (bFGF). Each cytokine has
distinctive, synergistic roles in tissue repair, as recent studies
involving in vivo gene transfection, gene disruption ("knockout"),
and the administration of cytokines have shown. Excessive cellular
proliferation may be induced by cytokines such as FGF-Beta-1
platelet-derived growth factor (PDGF), epidermal growth factor
(EGF), and/or fibroblast growth factor (TGF).
A central event in tissue repair is the release of cytokines in
response to injury. Transforming growth factor B (TGF-Beta-1) is a
key growth factor that initiates tissue repair and whose sustained
production underlies the development of tissue fibrosis (ref. 104,
105). (Copies attached.)
The regulation of TGF-Beta-1 secretion and action involves complex
post-transcriptional events, including messenger RNA (mRNA)
stabilization, the assembly and activation of the latent TGF-Beta-1
complex, and the modulation of receptor expression.
TGF-Beta-1 is unique in its widespread actions that enhance the
deposition of extracellular matrix. It also acts as a potent
regulator of repair, coordination or suppressing the actions of
other cytokines.
At physiologic concentrations, TGF-Beta-1 regulates PDGF (in
smooth-muscle cells and fibroblasts), FGF (in endothelial cells),
by stimulating or inhibiting their production or modulating their
actions to both synchronize and control the repair process.
TGF-Beta-1 consistently and potently acts on cells to induce the
deposition of extracellular matrix.
Immunological antagonists of transforming growth factor-Beta-1
prevent fibrosis. For instance, neutralizing anti-transforming
growth factor-B antibody inhibited scar formation in healing dermal
wounds and prevented the development of carotid initimal
hyperplasia after balloon angioplasty.
Measuring Inhibition of Fibroblast Proliferation
1. WI38 cells (50,000 per ml) were grown in 2.0 FBS for 24 hours
prior to addition of growth factor; thereafter, cultured for an
additional 72 hours. The cells were maintained in 2.0% FBS for the
entire experiment.
2. After culturing, 500 microliters of filtered neutral red (10
mg/100 ml) were added for 1 hour.
3. Monolayers were washed twice with warm PBS (saline) to remove
excess stain.
4. Adsorbed stain was extracted with a solution containing 50%
ethanol in 100 mM NaH.sub.2 PO.sub.4.
5. 200 microliters were removed from each treatment and added to
one well of a 96 well plate.
6. Optical density (O.D.) was read at 550 nm with a Biotek plate
reader.
7. Amount of stain retained by cells served as an index of cell
growth.
Inhibition of Growth Factor-Enhanced Fibroblast Proliferation
The enhanced proliferation of WI38 fibroblasts after exposure to
PDGF (platelet derived growth factor; or FGF (fibroblast growth
factor) was blocked by pirfenidone added to cell growth media.
Pirfenidone also inhibited the rise in collagen output by WI38
fibroblast cultures when induced by TGF-beta-1 (transforming growth
factor-beta-1). The enhanced proliferation of WI38 fibroblasts
after exposure to PDGF (platelet derived growth factor) or FGF
(fibroblast growth factor was blocked by pirfenidone added to cell
growth media.
TABLE 1 ______________________________________ INHIBITION BY
PIRFENIDONE OF ENHANCED PROLIFERATION INDUCED BY PLATELET DERIVED
GROWTH FACTOR (PDGF) IN HUMAN LUNG FIBROBLAST (WI38) CELL CULTURES
Platelet Derived Growth Factor (PDGF) (1.0 micrograms per ml) Plate
Treatment Optical Density
______________________________________
1. Control (C) 0.1278 +/- 0.0015 2. C + PDGF 0.1529 +/- 0.0026 3.
100 mcg pirfenidone (P) 0.1215 +/- 0.0047 4. 100 mcg P + PDGF
0.1129 +/- 0.0041 5. 300 mcg P 0.0968 +/- 0.0016 6. 300 mcg P +
PDGF 0.0934 +/- 0.0036 ______________________________________
Conclusions:
1. PDGF, 1.0 mcg/ml, significantly INCREASED cell
proliferation.
Student's T=8.36; P<0.01
2. Pirfenidone (100 mcgs per ml) alone significantly INHIBITED cell
proliferation, but not significantly.
Student's T=1.49; not significant statistically
3. Pirfenidone (300 mcgs per ml) alone significantly INHIBITED cell
proliferation.
Student's T=14.1; P<0.01
4. Pirfenidone (100 mcgs per ml) significantly INHIBITED the
INCREASED cell proliferation induced by 1.0 mcgs/ml of PDGF.
Student's T=8.16; P<0.01
5. Pirfenidone (300) mcgs per ml) significantly INHIBITED the
INCREASED cell proliferation induced by 1.0 mcgs/ml of PDGF.
Student's T=13.2; P<0.01
TABLE 2 ______________________________________ INHIBITION BY
PIRFENIDONE OF ENHANCED CELL PROLIFERATION INDUCED BY FIBROBLAST
GROWTH FACTOR (FGF) IN HUMAN LUNG FIBROBLAST (WI38) CELL CULTURES
(FGF, 0.5 micrograms [mcg] per ml) Plate Treatment Optical Density
______________________________________ 1. Control (C) 0.1389 +/-
0.0028 2. C + FGF 0.1514 +/- 0.0058 3. 100 mcg pirfenidone (P)
0.1206 +/- 0.0039 4. 100 mcg P + FGF 0.1018 +/- 0.0036 5. 300 mcg P
0.0936 +/- 0.0016 6. 300 mcg P + FGF 0.0963 +/- 0.0038
______________________________________
Conclusions:
1. FGF, 0.5 mcgs/ml, significantly INCREASED cell
proliferation.
Student's T=1.95; P+0.055
2. Pirfenidone (100 mcgs per ml) alone significantly INHIBITED cell
proliferation.
Student's T=2.61; P+0.02
3. Pirfenidone (300 mcgs per ml) alone significantly INHIBITED cell
proliferation.
Student's T=7.55; P<0.01
4. Pirfenidone (100 mcgs per ml) significantly INHIBITED the
INCREASED cell proliferation caused by 0.5 mcgs/ml of FGF.
Student's T=7.29; P<0.01
5. Pirfenidone (300 mcgs per ml) significantly INHIBITED the
INCREASED cell proliferation caused by 0.5 mcgs/ml of FGF.
Student's T=7.87; P<0.01
Collagen Purification
1. Media DMEM+10% FBS.
2. Ascorbic acid stock (100.times.) 5 mg/ml stored frozen, add 500
microliters/5 ml media just prior to use.
3. Prepare 0.025M Tris buffer (3 g/l) at pH 7.5 containing
5.times.10.sup.-5 (N-ethylmaleimide, Sigma) NEM (1-25 mg/ml).
Collagen in culture media (Use 24-well cluster plate)
1. Set up one 24-well plate using WI38 cells suspended in DMEM+10%
FBS+50 micrograms/ml ascorbic acid. Allow cells to grow to
confluency in 48-72 hours. Add 0.5 ml media per well.
2. Discard media and add new DMEM without FBS but with ascorbic
acid.
______________________________________ 6 control wells 0.5 ml new
media 6 pirfenidone wells Pirfenidone 0.2 mg/ml 6 TGF-beta wells
TGF beta-1 ng/ml 6 TGF-beta + pirfenidone Pirf. 0.2 mg/ml + TGF
beta 1 ng/ml ______________________________________
3. Add 2 microcuries of 3H Proline to all wells (or add 50
microliters of isotope solution containing 40 microcuries/ml media.
Incubate at 37.degree. C. CO.sub.2 incubator for 24 hours.
4. Collect medium from each well and dialyze separately (or pools)
using dialysis bags against Tris buffer (#3 above) with 3 exchanges
every 24 hours.
5. Collect dialysate and divide fluid from each bag into equal 0.3
ml aliquots.
6. Determine total counts of 3H for each well using one of three
0.3 ml aliquots.
7. With remaining two aliquots for each well, treat with or without
2.5 units collagenase (Advance Biofactures) for 18 hours at
37.degree. C. Add 0.6 ml of reaction mixture (0.025M Tris,
5.times.10.sup.-5 NEM, 1% BAS and 0.02M CaCl.sub.2).
8. Stop reaction by adding 200 microliters of solution containing
25% TCA+1.25% tannic acid to precipitate proteins.
9. Centrifuge to remove precipitate and count supernatants in
scintillation counter.
10. Express results relative to 3H incorporation in collagen.
Procedure of:
1. Peterofsky B and Diegelmann R., Biochemistry, 10, 988-994,
1971.
2. Russell J. D., Russell S. B., and Trupin K. M., J. Cell
Physiology, 97, 221-230, 1978.
Inhibition by Pirfenidone of Growth Factor-Enhanced Synthesis by
Fibroblasts of Collagen and GAG
TABLE 3 ______________________________________ INHIBITION BY
PIRFENIDONE OF ENHANCED COLLAGEN SYNTHESIS INDUCED BY TRANSFORMING
GROWTH FACTOR (TGF-B-1) (Cell cultures of human lung fibroblasts,
strain WI38) No. of Wells Mean
______________________________________ 1. Control 6 5.63 +/- 0.89
2. Pirfenidone only 6 3.77 +/- 0.89 3. TGF-B-1* only 6 10.60 +/-
2.17** 4. TGF-B-1* plus 5 6.28 +/- 2.13 Pirfenidone
______________________________________ *1.0 nanograms per ml.
**Only group differing significantly from Control (Group #1); P =
0.05.
Note: Cells were grown in PSB-free medium, pirfenidone was added on
day 0 and allowed 48-72 hours for cells to grow to confluency.
Radioactive proline (2 microcuries per well) was added 6 hours
before harvesting.
FIGS. 1A and 1B illustrate the effect of pirfenidone on
TGF-Beta-enhanced collagen (FIG. 1A) and glycosaminoglycans (GAG)
(FIG. 1B) synthesis in cultured human normal dermal fibroblasts.
Confluent cells were serum-starved for 24 hours and then treated
with TGF-Beta and pirfenidone for 6 hours at the indicated
concentrations. Incorporation of 3H proline (for collagen or 35
SO.sub.4 (for GAG) into medium and cell lysates were measured as
total synthesis. Results: *, **, and ***, p<0.05, 0.01, and
0.001, respectively, vs. a group treated with TGF-Beta alone
(Student's t-test).
FIGS. 2A and 2B illustrate the effect of pirfenidone on TGF-Beta-1
(200 pmol/l)-enhanced collagen (FIG. 2A) and glycosaminoglycan
(FIG. 2B) synthesis in cultured human normal dermal fibroblasts.
Each column indicates the mean =/-SE of five experiments. Results:
*, **, and ***, significantly different from the control (C) at
p<0, 00.5, 0.01, and 0.001, respectively.
FIG. 3 illustrates the effect of pirfenidone on DNA synthesis of
human skin fibroblast stimulated with 10% FBS (A) and PDGF-BB (B).
The data is expressed as mean =/-SE of six experiments. Results: *,
**, and ***, significantly different from control at p<0.05,
p<0.01, and p<0.001, respectively.
Effect on Collagen Syntheses in Cultured Human Prostate Stromal
Cells
Methods
Human hypertrophied prostate was cut into small pieces and digested
with 0.1% collagenase, 10% FBS in DMEM for 24 hours. Dispersed
cells were collected by centrifugation at 1000 rpm. Suspended cells
were centrifuged at 300 rpm and resulting supernatant which
contained stromal cells were collected. Stromal cells were cultured
in 10% FBS-DMEM. Confluent stromal cells were preincubated in
FBS-free medium for 24 hours. and incubated in FBS-free medium
containing 25 micrograms/ml of ascorbic acid and 80 micrograms/ml
of beta-aminopropionitrile for 24 hours. The conditioned media were
collected and the procollagen contents were determined using a
procollagen assay kit. Effects of pirfenidone on TGF-beta induced
procollagen production were investigated. Assays were performed in
triplicate.
Results
TGF-beta (10 nanograms/ml) increased procollagen content in
conditioned medium from human prostate stromal cells as illustrated
on FIG. 4. Pirfenidone (10-100 micrograms/ml) inhibited the
increase in procollagen content in a concentration dependent
manner.
FIGS. 5A and 5B illustrate the effect of pirfenidone on
proliferation of human lung fibroblast cells.
FIG. 6 illustrates the effect on proliferation of human lung
fibroblast (WI38) cells. Pirfenidone inhibited the cell
proliferation in a dose-dependent manner and ICso was calculated at
approximately 100 mcg/ml. On the other hand, no apparent cell death
was observed from vital staining even at 1,000 mcg/ml.
In addition to pirfenidone, N-substituted 2(1H) pyridones and
N-substituted 3(1H) pyridones have been found or are believed to
have efficacy in the prevention and treatment of disorders caused
by enhanced proliferation and enhanced biosynthesis caused by
cytokine growth factors.
The general structural formula for the 2 pyridones is: ##STR1##
where: R1=alkyl group (CH3, C2H5, etc.); A is phenyl, thienyl,
etc., or other aryl group. The alternate is for R3 to be the site
of substitution of the alkyl group with R1 remaining as a hydrogen;
R2 and R4 are, in every circumstance, hydrogens.
The general structural formual for the 3 pyridones is: ##STR2##
where: R2 or R3=alkyl group or hydrogen, as above; A is phenyl,
thienyl, etc., or other aryl. R1 and R4 are hydrogen.
Examples of the 2 and 3 pyridones include:
5-Methyl-1-(3-nitrophenyl-2)-(1H) pyridone
5-Methyl-1-(4'-methoxyphenyl)-2-(1H) pyridone
5-Methyl-1-p-tolyl-2-(1H) pyridone
5-Methyl-1-(3'-trifluoromethylphenyl)-2-(1H) pyridone
1-(4'Chlorophenyl)-5-Methyl-2)-(1H) pyridone
5-Methyl-1-(2'-naphthyl)-2-(1H) pyridone
5-Methyl-1-(1'naphthyl)-2-(1H) pyridone
3-Methyl-1-phenyl-2-(1H) pyridone
3-Ethyl-1-phenyl-2-(1H) pyridone
6-Methyl-1-phenyl-2-(1H) pyridone
3,6-Dimethyl-1-phenyl-2-(1H) pyridone
5-Methyl-1-(2'-Thienyl)-2-(1H) pyridone
1-(2'-Furyl)-5-Methyl-2-(1H) pyridone
5-Methyl-1-(5'-quinolyl)-2-(1H) pyridone
5-Methyl-1-(4'-pyridyl)-2-(1H) pyridone
5-Methyl-1-(3'-pyridyl)-2-(1H) pyridone
5-Methyl-1-(2'-pyridyl)-2-(1H) pyridone
5-Methyl-1-(2'-quinolyl)-2-(1H) pyridone
5-Methyl-1-(4'-quinolyl)-2-(1H) pyridone
5-Methyl-1-(2'-thiazolyl)-2-(1H) pyridone
1-(2'-Imidazolyl)-5-Methyl-2-(1H) pyridone
5-Ethyl-1-phenyl-2-(1H) pyridone
1-Phenyl-2-(1H) pyridone
1-(4'-Nitrophenyl)-2-(1H) pyridone
1,3-Diphenyl-2-(1H) pyridone
1-Phenyl-3-(4 -chlorophenyl)-2-(1H) pyridone
1,3-Diphenyl-5-methyl-2-(1H) pyridone
3-(4'-Chlorophenyl)-5-Methyl-1-phenyl-2-(1H) pyridone
5-Methyl-3-phenyl-1-(2'-thienyl)-2-(1H) pyridone
5-Methyl-1-phenyl-3-(1H) pyridone
5-Methyl-1-(4'-methoxyphenyl)-3-(1H) pyridone
5-Methyl-1-p-tolyl-3-(1H) pyridone
1-(4'-Chlorophenyl)-5-methyl-3-(1H) pyridone
5-Methyl-1-(2'-naphthyl)-2-(1H) pyridone
4-Methyl-1-phenyl-3-(1H) pyridone
6-Methyl-1-phenyl-3-(1H) pyridone
5-Methyl-1(2'-Thienyl)-3-(1H) pyridone
1-(2'-Furyl)-5-methyl-3-(1H) pyridone
5-Methyl-1-(5'-quinolyl)-3-(1H) pyridone
5-Methyl-1-(3'-pyridyl)-3-(1H) pyridone
5-Methyl-1-(2'-pyridyl)-3-(1H) pyridone
5-Methyl-1-(2'-quinolyl)-3-(1H) pyridone
5-Ethyl-1-phenyl-3-(1H) pyridone
1-Phenyl-3-(1H) pyridone
These compounds can be prepared using methods similar to those set
forth in U.S. Pat. No. 3,839,346, issued Oct. 1, 1974, to Gadekar,
and titled N-SUBSTITUTED PYRIDONE AND GENERAL METHOD FOR PREPARING
PYRIDONES, the disclosure of which is incorporated by reference
hereinto. That patent also describes use of some of those compounds
in analgesic, anti-inflammatory, and antipyretic treatments. U.S.
Pat. No. 3,974,281, issued Aug. 10, 1976; U.S. Pat. No. 4,042,699,
issued Aug. 16, 1977; and U.S. Pat. No. 4,052,509, issued Oct. 4,
1988, all to Gadekar, describe further use of pirfenidone in
lowering serum uric acid and glucose levels, treating upper
respiratory inflammatory conditions, and treating inflammatory skin
conditions, in humans and other animals. U.S. Pat. No. 5,310,562,
issued May 10, 1994, to Margolin, and titled COMPOSITION AND METHOD
FOR REPARATION AND PREVENTION OF FIBROTIC LESIONS, and copending
U.S. application Ser. No. 08/243,058, by Margolin, and titled
COMPOSITIONS AND METHODS FOR REPARATION AND PREVENTION OF FIBROTIC
LESIONS disclose the use of the above compounds in the reparation
and prevention of fibrotic lesions.
In laboratory animals, the oral effective dose in the various
disorders mentioned above ranges from about 20 to about 150 mg/kg
body weight per day in divided dosage. The wide range is due to the
fact tha, in rodents (mice, rats, guinea pigs, hamsters, and
rabbits), the drug is very rapidly
metabolized and thus higher dosages are required. In dogs (who have
a metabolic drug intake very similar to humans) and in humans, the
daily dosage is in the range of 10-75 mg/kg body wieght per day in
divided dosage.
The compositions of the present invention may be administered in
forms consisting of capsules, tablets, powders, granules, syrups,
aerosols, injectable fluids, pills, creams, ointments, inhalable
fluids, eye drops, and suppositories.
It will thus be seen that the objects set forth above, among those
elucidated in, or made apparent from, the preceding description,
are efficiently attained and, since certain changes may be made in
the above compositions and methods without departing from the scope
of the invention, it is intended that all matter contained in the
foregoing disclosure shall be interpreted as illustrative only and
not in a limiting sense.
It is also to be understood that the following claims are intended
to cover all of the generic and specific features of the invention
herein described and all statements of the scope of the invention
which, as a matter of language, might be said to fall
therebetween
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